We have previously shown that cellular glutathione (GSH) regulates the T- cell proliferative activity of Interleukin-2 (IL-2). Here, we examined whether and how GSH affects the activity of Interleukin-4 (IL-4) on murine cytotoxic T cells. CT.4R, a T cell line that is responsive to both IL-4 and IL-2, was used as a model. Although GSH alone had little effect on the thymidine incorporation of CT.4R cells, it enhanced the response of CT.4R to IL-4 and increased the level of thymidine incorporation up to more than 60 fold in a concentration-dependent manner. GSH affected the binding of IL-4 to cellular receptors. Scatchard plot analysis showed that GSH treatment did not change the dissociation constant significantly, however it increased the receptor number from 1173 +/- 126 To 2112 +/- 492 molecules per cell. Internalization and degradation studies of IL-4 showed that the amount of IL-4 internalized and degraded in the GSH treated cells was about 2-fold higher than those in the cells without GSH treatment. These results suggest that GSH regulates the binding, internalization, degradation, and T-cell proliferative activity of IL-4; alteration of cellular GSH levels may thus affect the growth and replication of cytotoxic T cells through growth stimulating cytokines such as IL-2 and IL-4.